STOCKHOLM – The use of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with type 1 diabetes looks promising despite concerns over their potential to cause diabetic ketoacidosis (DKA), experts reported here at the annual meeting of the European Association for the Study of Diabetes.
Results of three trials, including the results of an 18-week phase II trial with canagliflozin, a 4-week phase II trial with sotagliflozin, and a 4-week phase II trial with empagliflozin showed that these drugs are effective when used in addition to insulin to lower hemoglobin A1c and have the added benefit of weight-reduction without increasing the risk for hypoglycemia.
“We must be very careful about using SGLT2 inhibitors in type 1 diabetes,” said Dr. David Matthews, professor of diabetes, emeritus founding chairman, Oxford (England) Centre for Diabetes, Endocrinology and Metabolism, in an interview. “These are preliminary studies, you’d have to use it off label, and you’d have to take responsibility for being very careful about the induction of DKA,” he observed.
Dr. Matthews, who chaired the session during which the canagliflozin results were presented, added: “DKA is clearly one of the risks, and we’ve learned a lot about why this might occur, for instance when there are the additional risks such as illness or with the use of anesthesia.”
DKA: Why the concern?
SGLT2 inhibitors are currently approved for use only in patients with type 2 diabetes when diet and exercise alone are not able to help patients achieve sufficient glycemic control. Recently, however, their potential to cause ketoacidosis even in patients with type 2 diabetes were the focus of a Drug Safety Communication issued by the Food and Drug Administration. The warning applied to all currently available SLGT2 preparations: canagliflozin (Invokana), canagliflozin/metformin (Invokamet), dapagliflozin (Farxiga), dapagliflozin/metformin extended release (Xigduo XR), empagliflozin (Jardiance), and empagliflozin/lingagliptin (Glyxambi); similar warnings followed from the European Medicines Agency.
Dr. Matthews observed that the risk of DKA in patients with type 2 diabetes may be clouded by patients with type 1 being misdiagnosed. “In type 2 diabetes, there is clearly a mix of people with type 1 whom you misdiagnose or who have got latent type 1 diabetes. Those are often the people on insulin, so they fall into the category of type 2 diabetes, and almost by mistake you are treating people with type 1 diabetes.”
Dr. Anne L. Peters
Dr. Anne L. Peters of the University of Southern California, Los Angeles, and author of a recent article (Diabetes Care. 2015 Sep;38[9]:1687-93) highlighting the risk for DKA among type 2 diabetics treated with SGLT2 inhibitors, noted that use in type 1 diabetes had been shown to improve glucose control.
“Frankly, we know they work,” she said. “We know that they work in people with type 2 diabetes, and you are about to find out that they work in patients with type 1 diabetes, at least in a phase II trial,” Dr. Peters added.
“We know that the mechanism of action is insulin independent and, by design, [SGLT2 inhibitors] can work in both type 1 and type 2 diabetes,” she said. “But we also know that when we use [these agents] off label in diabetes that there is a signal for an increased risk for diabetic ketoacidosis.”
However, in her experience of using canagliflozin, every case of DKA involved “precipitating factors.” These included infections such as influenza or pneumonia that resulted in the patient not being well and not eating and thus reducing their insulin use or device or compliance issues resulting in reduced insulin dosing.
Dr. Peters suggested that should off-label use be considered outside of a clinical trial, patients must be adherent to routine glucose and ketone testing. She noted that she advised her patients to hold off using an SGLT2 inhibitor if they were going to be doing something different, such being more physically active, or if they had been ill and their insulin dosing had decreased.
Canagliflozin: Phase II study
Dr. Robert R. Henry
Dr. Robert R. Henry, professor of medicine at the University of California, San Diego, presented the results of an 18-week, phase II study with canagliflozin, which was completed in June and accepted for publication in Diabetes Care. The double-blind, placebo-controlled, multicenter study involved 351 randomized patients with type 1 diabetes and a mean age of roughly 42 years treated with canagliflozin 100 mg (n = 117), canagliflozin 300 mg (n = 117), or placebo (n =1 17).
The primary efficacy endpoint was the proportion of patients with a decrease in HbA1c of 0.4% or more and no increase in body weight. This combined endpoint was met by 37% and 41% of the 100-mg and 300-mg canagliflozin-treated patients, respectively, and by 15% of those randomized to placebo (both P less than .001 vs. placebo). Considering each of the components separately showed that a higher percentage of patients achieved an HbA1c reduction of 0.4% or more (43%-45% vs. 23%) and reduced body weight (84%-96% vs. 49%).